Abstract: Cardiac arrhythmias are a major cause of morbidity and mortality. Arrhythmias occur when the normal flow of electricity in the heart becomes disordered. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) provide a unique model system for investigating arrhythmic disorders [1]. As a research model, hiPSC-CMs have a number of advantages in that they are human (and patient specific) in origin, provide an alternative to using cardiomyocytes derived from animals, are genetically editable, and can provide a near renewable supply of cells. However, in comparison to adult cardiomyocytes, hiPSC-CMs are structurally and electrophysiologically immature and exhibit a late foetal phenotype [2,3]. Our view, is that the immaturity of hiPSC-CMs currently hampers their utility as a model system in which to study the mechanisms underlying arrhythmias. Excitingly, a number of protocols have recently been published (for example [4] and [5]) that enable significant and accelerated structural and functional maturation of hiPSC-CMs. However, whether this maturation leads to an improved electrophysiological phenotype has not been determined. In this project the student will explore whether these maturation protocols (and other approaches), when applied singly or in combination, act to improve the electrophysiological phenotype of hiPSC-CMs. To achieve this, the structural maturation of hiPSC-CMs will be determined using immunostaining and confocal laser scanning microscopy (CLSM) and the patch-clamp technique will be used to characterise the electrophysiological phenotype. In summary, if hiPSC-CMs can be matured to achieve an improved electrophysiological phenotype this will greatly enhance the translational utility of this already exciting heart-in-a-dish technology for modelling a wide-range of cardiovascular disorders.
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